Spiro-lactam nmda receptor modulators and uses thereof

ABSTRACT

Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/757,939, filed on Jan. 29, 2013, which is incorporated by referencein its entirety.

BACKGROUND

N-methyl-d-aspartate (NMDA) receptor is a postsynaptic, ionotropicreceptor that is responsive to, inter alia, the excitatory amino acidsglutamate and glycine and the synthetic compound NMDA. The NMDA receptorcontrols the flow of both divalent and monovalent ions into thepostsynaptic neural cell through a receptor associated channel (Fosteret al., Nature 1987, 329:395-396; Mayer et al., Trends in Pharmacol.Sci. 1990, 11:254-260). The NMDA receptor has been implicated duringdevelopment in specifying neuronal architecture and synapticconnectivity, and may be involved in experience-dependent synapticmodifications. In addition, NMDA receptors are also thought to beinvolved in long term potentiation and central nervous system disorders.

The NMDA receptor plays a major role synaptic plasticity that underliesmany higher cognitive functions, such as memory acquisition, retentionand learning, as well as in certain cognitive pathways and in theperception of pain (Collingridge et al., The NMDA Receptor, OxfordUniversity Press, 1994). In addition, certain properties of NMDAreceptors suggest that they may be involved in theinformation-processing in the brain that underlies consciousness itself.

The NMDA receptor has drawn particular interest since it appears to beinvolved in a broad spectrum of CNS disorders. For instance, duringbrain ischemia caused by stroke or traumatic injury, excessive amountsof the excitatory amino acid glutamate are released from damaged oroxygen deprived neurons. This excess glutamate binds to the NMDAreceptors which opens their ligand-gated ion channels; in turn thecalcium influx produces a high level intracellular calcium whichactivates a biochemical cascade resulting in protein degradation andcell death. This phenomenon, known as excitotoxicity, is also thought tobe responsible for the neurological damage associated with otherdisorders ranging from hypoglycemia and cardiac arrest to epilepsy. Inaddition, there are preliminary reports indicating similar involvementin the chronic neurodegeneration of Huntington's, Parkinson's, andAlzheimer's diseases. Activation of the NMDA receptor has been shown tobe responsible for post-stroke convulsions, and, in certain models ofepilepsy, activation of the NMDA receptor has been shown to be necessaryfor the generation of seizures. Neuropsychiatric involvement of the NMDAreceptor has also been recognized since blockage of the NMDA receptorCa⁺⁺ channel by the animal anesthetic PCP (phencyclidine) produces apsychotic state in humans similar to schizophrenia (reviewed in Johnson,K. and Jones, S., 1990). Further, NMDA receptors have also beenimplicated in certain types of spatial learning.

The NMDA receptor is believed to consist of several protein chainsembedded in the postsynaptic membrane. The first two types of subunitsdiscovered so far form a large extracellular region, which probablycontains most of the allosteric binding sites, several transmembraneregions looped and folded so as to form a pore or channel, which ispermeable to Ca⁺⁺ and a carboxyl terminal region. The opening andclosing of the channel is regulated by the binding of various ligands todomains (allosteric sites) of the protein residing on the extracellularsurface. The binding of the ligands is thought to affect aconformational change in the overall structure of the protein which isultimately reflected in the channel opening, partially opening,partially closing, or closing.

NMDA receptor compounds may exert dual (agonist/antagonist) effect onthe NMDA receptor through the allosteric sites. These compounds aretypically termed “partial agonists”. In the presence of the principalsite ligand, a partial agonist will displace some of the ligand and thusdecrease Ca⁺⁺ flow through the receptor. In the absence of or loweredlevel of the principal site ligand, the partial agonist acts to increaseCa⁺⁺ flow through the receptor channel.

A need continues to exist in the art for novel and more specific/potentcompounds that are capable of binding the glycine binding site of NMDAreceptors, and provide pharmaceutical benefits. In addition, a needcontinues to exist in the medical arts for orally deliverable forms ofsuch compounds.

SUMMARY

Provided herein, at least in part, are compounds that are NMDAmodulators, for example, partial agonists of NMDA. For example,disclosed herein are compounds represented by the formula:

-   and pharmaceutically acceptable salts, stereoisomers, and N-oxides    thereof, wherein-   R_(b) is selected from the group consisting of H, halogen, hydroxyl,    cyano and C₁-C₆ alkyl;-   R is H or C₁-C₆ alkyl;-   R₁ is H or C₁-C₆ alkyl;-   R₂ is H or C₁-C₆ alkyl;-   R₃ is selected from the group consisting of H, C₁-C₆ alkyl, —OH,    C₁-C₆alkoxy, —CO₂H, or —CONR′R′, wherein R′ for each occurrence is    selected from H, C₁-C₆ alkyl or a nitrogen protecting group; and-   X is H or —C₁C₆ alkylene-C(O)—X′, wherein X′ is selected from the    group consisting of C₃-C₆ cycloalkyl, a 4- to 6-membered    heterocycloalkyl ring having 1, 2, or 3 heteroatoms selected from O,    S, or N, phenyl and 4- to 6-membered heteroaryl ring having 1, 2, or    3 heteroatoms selected from O, S, or N, wherein X′ is optionally    substituted by one or more substituents selected front the group    consisting of halogen, hydroxyl, C₁-C₆ alkyl and C₁-C₆ alkoxy; or in    other embodiments, the variables set forth in formula (I) can be as    defined as follows:-   R_(b) is selected from the group consisting of H, halogen, hydroxyl,    cyano and C₁-C₆ alkyl;-   R is H or C₁-C₆ alkyl;-   R₁ is H or C₁-C₆ alkyl;-   R₂ is H or C₁-C₆ alkyl;-   R₃ is selected from the group consisting of H, C₁-C₆ alkyl, —OH,    C₁-C₆ alkoxy, —CO₂H, or —CONR′R′, wherein R′ for each occurrence is    independently selected from H, C₁-C₆ alkyl or a nitrogen protecting    group; and-   X is H, X′, alkylene-X′, or —C₁-C₆ alkylene-C(O)—X′, wherein X′ is    selected from the group consisting of:-   (i) C₃-C₆ cycloalkyl;-   (ii) heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or    3 of the ring atoms are independently selected from the group    consisting of N, NH, N(C1-C3 alkyl), O and S;-   (iii) phenyl; and-   (iv) heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3    of the ring atoms are independently selected from the group    consisting of N, NH, N(C1-C3 alkyl), O, and S;-   wherein X′ is optionally substituted by one, two or three    substituents independently selected from the group consisting of    halogen, hydroxyl, C₁-C₆ alkyl and C₁-C₆ alkoxy.

In another aspect, disclosed compounds include those represented by theformula:

-   and pharmaceutically acceptable salts, stereoisomers, and N-oxides    thereof, wherein-   R_(b) is selected from the group consisting of H, halogen, hydroxyl,    cyano and C₁-C₆ alkyl;-   R is H or methyl;-   R₁ is H or methyl;-   R₂ is H or methyl;-   R₃ is selected from the group consisting of H, C₁-C₆ alkyl, —OH,    C₁-C₆ alkoxy, —CO₂H, or —CONR′R′, wherein R′ for each occurrence is    selected from H, C₁-C₆ alkyl or a nitrogen protecting group; and-   X is H or —C₁-C₆ alkylene-C(O)—NR^(c)R^(d);-   R^(c) and R^(d), together with the nitrogen to which they are    attached, form a 4-6 membered heterocyclic ring, which may have an    additional heteroatom selected from O, S, or N; wherein the 4-6    membered heterocyclic ring may optionally be substituted by one or    more substituents selected from the group consisting of halogen,    cyano, oxo, and C₁-C₆alkyl.

Also provided herein are pharmaceutically acceptable compositionscomprising a disclosed compound, and a pharmaceutically acceptableexcipient. For example, such compositions may be suitable for oral orintravenous administration to a patient.

In another aspect, a method of treating a condition selected from thegroup consisting of autism, anxiety, depression, bipolar disorder,attention deficit disorder, attention deficit hyperactivity disorder(ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, socialwithdrawal, obsessive-compulsive disorder, phobia, post-traumatic stresssyndrome, a behavior disorder, an impulse control disorder, a substanceabuse disorder, a sleep disorder, a memory disorder, a learningdisorder, urinary-incontinence, multiple system atrophy, progressivesupra-nuclear palsy, Friedrich's ataxia, Down's syndrome, fragile Xsyndrome, tuberous sclerosis, olivio-ponto-cerebellar atrophy, cerebralpalsy, drug-induced optic neuritis, ischemic retinopathy, diabeticretinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease,Huntington's chorea, spasticity, myoclonus, muscle spasm, Tourette'ssyndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumaticbrain injury, cardiac arrest, myelopathy, spinal cord injury, peripheralneuropathy, acute neuropathic pain, and chronic neuropathic, in apatient in need thereof is provided. Such methods may compriseadministering to the patient a pharmaceutically effective amount of adisclosed compound or pharmaceutically acceptable salts, stereoisomers,N-oxides, and hydrates thereof.

In some embodiments, a contemplated method includes treating depression.For example, depression may include one or more of major depressivedisorder, dysthymic disorder, psychotic depression, postpartumdepression, seasonal affective disorder, bipolar disorder, mooddisorder, or depression caused by a chronic medical condition. In otherembodiments, a contemplated method may treat schizophrenia. Suchschizophrenia may be, for example, paranoid type schizophrenia,disorganized type schizophrenia, catatonic type schizophrenia,undifferentiated type schizophrenia, residual type schizophrenia,post-schizophrenic depression, or simple schizophrenia.

DETAILED DESCRIPTION

This disclosure is generally directed to compounds that are capable ofmodulating NMDA, NMDA antagonists or partial agonists, and compositionsand/or methods of using the disclosed compounds.

Definitions

“Treating” includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder and the like.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having t least one carbon-carbon double bond, suchas a straight or branched group of 2-6 or 3-4 carbon atoms, referred toherein for example as C₂-C₆alkenyl, and C₃-C₄ alkenyl, respectively.Exemplary alkenyl groups include, but are not limited to, vinyl, allyl,butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkylgroup attached to an oxygen (alkyl-O—). Exemplary alkoxy groups include,but are not limited to, alkoxys of 1-6 or 2-6 carbon atoms, referred toherein as C₁-C₆ alkoxy, and C₂-C₆ alkoxy, respectively. Exemplary alkoxygroups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

The term “alkenyloxy” used herein refers to a straight or branchedalkenyl group attached to an oxygen (alkenyl-O). Exemplary alkoxy groupsinclude, but are not limited to, groups with an alkenyl group of 3-6carbon atoms, (also e.g. referred to as C₃-C₆alkenyloxy). Exemplary“alkoxy” groups include, but are not limited to allyloxy, butenyloxy,etc.

The term “alkynyloxy” used herein refers to a straight or branchedalkynyl group attached to an oxygen (alkynyl-O)). Exemplary alkynyloxygroups include, but are not limited to, C₃-C₆alkynyloxy, e.g.,propynyloxy.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-6, 1-4,or 1-3 carbon atoms, referred to herein as C₁-C₆alkyl, C₁-C₄alkyl, andC₁-C₃alkyl, respectively. Exemplary alkyl groups include, but are notlimited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, etc. The term “haloalkyl” as used herein refers to a saturatedstraight or branched alkyl groups, in which one or more hydrogen atomsof the alkyl group are replaced with one or more independently selectedhalogens. The term “haloalkyl” encompasses alkyl groups in which all ofhydrogen atoms of the alkyl group are replaced independently selectedhalogens (sometimes referred to as “perhalo” alkyl groups. Exemplaryhaloalkyl groups include, but are not limited to, CH₂F, CH₂CH₂Cl, CF₃,CHFCH₂Cl.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-6, or 3-6 carbon atoms, referred toherein as C₂-C₆alkynyl, and C₃-C₆alkynyl, respectively. Exemplaryalkynyl groups include, but are not limited to, ethynyl, propynyl,butynyl, pentynyl, hexynyl, methylpropynyl, etc.

The term “bridged cycloalkyl” as used herein, is defined as a monocyclic4- to 7-membered cycloalkyl group in which two non-adjacent atoms arelinked by a CH₂ or CH₂CH₂ group. A “bridged cycloalkyl” may be fused toone or more phenyl, partially unsaturated, or saturated rings. Examplesof bridged carbocyclic groups include but are not limited tobicyclo[2.2,1]heptane, bicyclo[2.2.2]octane bicyclo[2.2.2]octene etc.

The term “carbonyl” as used herein refers to the radical —C(O)—. Theterm “cyano” as used herein refers to the radical —CN. The term “nitro”refers to the radical —NO₂. The term “H” refers to hydrogen.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to an oxygen (cycloalkyl-O—).

The term “cycloalkyl” as used herein refers to a monocyclic saturated orpartically unsatured hydrocarbon group of for example 3-6, or 4-6carbons, referred to herein, e.g., as “C₃₋₆ cycloalkyl” or“C₄₋₅cycloalkyl,” and derived from a cycloalkane. Exemplary cycloalkylgroups include, but are not limited to, cyclohexyl, cyclohexenyl,cyclopentyl, cyclobutyl, cyclopropyl or cyclopentyl.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The terms “heteroaryl” as used herein refers to a monocyclic aromatic4-6 membered ring system containing one or more heteroatoms, for exampleone to three heteroatoms, such as nitrogen, oxygen, and sulfur. Wherepossible, said heteroaryl ring may be linked to the adjacent radicalthough carbon or nitrogen. Examples of heteroaryl rings include but arenot limited to furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl,isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), pyridyl, andpyrimidinyl.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized andrefer to saturated or partially unsaturated 4- to 7-membered ringstructures, whose ring structures include one to three heteroatoms, suchas nitrogen, oxygen, and sulfur. A heterocycle may be fused to one ormore phenyl, partially unsaturated, or saturated rings. Examples ofheterocyclyl groups include but are not limited to pyrrolidinyl,piperidinyl, morpholino, thiomorpholino, and piperazinyl.

The term “heterocyclylalkoxy” as used herein refers to aheterocyclyl-alkyl-O— group.

The term “heterocyclyloxyalkyl” refers to a heterocyclyl-O-alkyl— group.

The term “heterocycloxy” refers to a heterocyclyl-O— group. The term“cycloalkyloxy” refers to a cycloalkyl-O— group.

The term “heteroaryloxy” referes to a heteroaryl-O— group.

The terms “hydroxy” and “hydroxyl” as used herein refers to the radical—OH.

The term “oxo” as used herein refers to the radical ═O.

The term “nitrogen protecting group” or “amino protecting group” isart-recognized and as used herein refers to a chemical moiety that iscovalently linked to a nitrogen atom of an amino (primary or secondary)group and that temporarily blocks the reactivity of the amino groupduring a synthetic step and is selectively removed once the syntheticstep is complete. Nitrogen protecting groups include, for example,9-Fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc),carbobenzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, acetyl,trifluoroacetyl, benzoyl, phthalimido, benzyl (Bn), p-methoxybenzyl,p-methoxyphenyl, 3,4-dimethoxybenzyl, triphenylmethyl, benzylidene, andp-toluenesulfonyl (Ts). In some embodiments, the nitrogen protectinggroup can have one of the following formulas: —C(O)OR₃₁ or C(O)R₃₂ asdefined herein. In certain embodiments, R₃₁ is selected from the groupconsisting of: C_(l)-C₆ alkyl; C₁-C₆ haloalkyl; C₂-C₆ alkenyl; C₂-C₆alkynyl; C₃-C₁₀ cycloalkyl, wherein the C₃-C₁₀ cycloalkyl is optionallysubstituted with from 1-3 independently selected C₁-C₃ alkyl;—CH₂-C₃-C₁₀ cycloalkyl wherein the C₃-C₁₀ cycloalkyl is optionallysubstituted with from 1-3 independently selected C₁-C₃ alkyl;—CH₂-phenyl, wherein the phenyl is optionally substituted with from 1-2substituents independently selected from C₁-C₃ C_(l)-C₃ haloalkyl, C₁-C₃alkoxy, C₁-C₃ haloalkoxy, nitro, halo, SO₂Me, cyano, and —OC(O)CH₃; and—CH₂-pyridyl. In certain embodiments, R₃₂ is selected from the groupconsisting of: H; C₁-C₆ alkyl; C₁-C₆ haloalkyl; phenyl, wherein thephenyl is optionally substituted with from 1-2 substituentsindependently selected from C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy,C₁-C₃ haloalkoxy, nitro, halo, SO₂Me, cyano, and —OC(O)CH₃; and pyridyl.

As used in the present disclosure, the term “partial NMDA receptoragonist” generally refers to a compound that is capable of binding to aglycine binding site of an NMDA receptor; at low concentrations a NMDAreceptor agonist acts substantially as agonist and at highconcentrations it acts substantially as an antagonist. Theseconcentrations are experimentally determined for each and every “partialagonist.

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, general safety and purity standards as requiredby FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein refers to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The compositions may also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The term “pharmaceutical composition” as used herein refers to acomposition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

“Individual,” “patient,” or “subject” are used interchangeably andinclude any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans. The compounds of the invention can beadministered to a mammal, such as a human, but can also be administeredto other mammals such as an animal in need of veterinary treatment,e.g., domestic animals (e.g., dogs, cats, and the like), farm animals(e.g., cows, sheep, pigs, horses, and the like) and laboratory animals(e.g., rats, mice, guinea pigs, and the like). The mammal treated in themethods of the invention is desirably a mammal in which treatment e.g.,of pain or depression is desired. “Modulation” includes antagonism(e.g., inhibition), agonism, partial antagonism and/or partial agonism.

In the present specification, the term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. The compounds of the invention are administered intherapeutically effective amounts to treat a disease. Alternatively, atherapeutically effective amount of a compound is the quantity requiredto achieve a desired therapeutic and/or prophylactic effect, such as anamount which results in lessening a symptom of depression.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be present in compounds used inthe present compositions. Compounds included in the present compositionsthat are basic in nature are capable of forming a wide variety of saltswith various inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate,salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds included in the present compositions that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts and, particularly, calcium, magnesium,sodium, lithium, zinc, potassium, and iron salts. Compounds included inthe present compositions that include a basic or acidic moiety may alsoform pharmaceutically acceptable salts with various amino acids. Thecompounds of the disclosure may contain both acidic and basic groups;for example, one amino and one carboxylic acid group. In such a case,the compound can exist as an acid addition salt, a zwitterion, or a basesalt.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diasteremners. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as geometric isomers,enantiomers or diastereomers. The enantiomer and diastereomers may bedesignated by the symbols “(+” “(−)” “R” or “S,” depending on theconfiguration of substituents around the stereogenic carbon atom, butthe skilled artisan will recognize that a structure may denote a chiralcenter implicitly. Geometric isomers, resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a cycloalkyl or heterocyclic ring, can also exist inthe compounds of the present invention. The symbol

denotes a bond that may be a single, double or triple bond as describedherein. Substituents around a carbon-carbon double bond are designatedas being in the “Z” or “E” configuration wherein the terms “Z” and “E”are used in accordance with IUPAC standards. Unless otherwise specified,structures depicting double bonds encompass both the “E” and “Z”isomers. Substituents around a carbon-carbon double bond alternativelycan be referred to as “cis” or “trans,” where “cis” representssubstituents on the same side of the double bond and “trans” representssubstituents on opposite sides of the double bond. The arrangement ofsubstituents around a carbocyclic ring can also be designated as “cis”or “trans.” The term “cis” represents substituents on the same side ofthe plane of the ring and the term “trans” represents substituents onopposite sides of the plane of the ring. Mixtures of compounds whereinthe substituents are disposed on both the same and opposite sides ofplane of the ring are designated “cis/trans.”

The term “stereoisomers” when used herein consist of all geometricisomers, enantiomers or diastereomers. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.

Individual enantiomers and diasteriomers of compounds of the presentinvention can be prepared synthetically from commercially availablestarting materials that contain asymmetric or stereogenic centers, or bypreparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture of diastereomersby recrystallization or chromatography and liberation of the opticallypure product from the auxiliary, (2) salt formation employing anoptically active resolving agent, (3) direct separation of the mixtureof optical enantiomers on chiral liquid chromatographic columns or (4)kinetic resolution using steroselective chemical or enzymatic reagents.Racemic mixtures can also be resolved into their component enantiomersby well-known methods, such as chiral-phase gas chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the ad. Stereoselective syntheses encompass both enantio-and diastereoselective transformations. For examples, see Carreira andKvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim,2009.

The compounds disclosed herein can exist in solvated as well asunsolvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. In one embodiment, thecompound is amorphous. In one embodiment, the compound is a singlepolymorph. In another embodiment, the compound is a mixture ofpolymorphs. In another embodiment, the compound is in a crystallineform.

The invention also embraces isotopically labeled compounds of theinvention are identical to those recited herein, except that one or moreatoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸ O,¹⁸O, ³¹P, ³²P, ³⁵S, ¹³F, and ³⁶Cl, respectively. For example, a compoundof the invention may have one or more H atom replaced with deuterium.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the e.g. Examples herein by substituting an isotopicallylabeled reagent for a non-isotopically labeled reagent.

The, term “prodrug” refers to compounds that are transformed in vivo toyield a disclosed compound or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (such as by esterase, amidase, phosphatase, oxidativeand or reductive metabolism) in various locations (such as in theintestinal lumen or upon transit of the intestine, blood or liver).Prodrugs are well known in the art (for example, see Rautio,Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). Forexample, if a compound of the invention or a pharmaceutically acceptablesalt, hydrate or solvate of the compound contains a carboxylic acidfunctional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a compound of the invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl(C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a compound of the invention incorporates an amine functional group, aprodrug can be formed, for example, by creation of an amide orcarbamate, an N-acyloxyakyl derivative, an (oxodioxolenyl)methylderivative, an N-Mannich base, imine or enamine. In addition, asecondary amine can be metabolically cleaved to generate a bioactiveprimary amine, or a tertiary amine can metabolically cleaved to generatea bioactive primary or secondary amine. For examples, see Simplicio, etal., Molecules 2008, 13, 519 and references therein.

Compounds

Disclosed compounds include those represented by the formula:

and pharmaceutically acceptable salts, stereoisomers, and N-oxidesthereof, wherein

R_(b) is selected from the group consisting of H, halogen, hydroxyl,cyano and C₁-C₆ alkyl;

R is H or C₁-C₆ alkyl;

R₁ is H or C₁-C₆ alkyl;

R₂ is H or C₁-C₆ alkyl;

R₃ is selected from the group consisting of H, C₁-C₆ alkyl, —OH, C₁-C₆alkoxy, —CO₂H, or —CONR′R′, wherein R′ for each occurrence is selectedfrom H, C₁-C₆ alkyl or a nitrogen protecting group; and

X is H or —C₁-C₆ alkylene-C(O)—X′, wherein X′ is selected from the groupconsisting of C₃-C₆ cycloalkyl, a 4- to 6-membered heterocycloalkyl ringhaving 1, 2, or 3 heteroatoms selected from O, S, or N, phenyl and 4- to6-membered heteroaryl ring having 1, 2, or 3 heteroatoms selected fromO, S, or N, wherein X′ is optionally substituted by one or moresubstituents selected from the group consisting of halogen, hydroxyl,C₁-C₆alkyl and C₁-C₆alkoxy;

or in other embodiments, the variables set forth in formula (I) can beas defined as follows:

R_(b) is selected from the group consisting of H, halogen, hydroxyl,cyano and C₁-C₆ alkyl (e.g., H);

R is H or C₁-C₆ alkyl;

R₁ is H or C₁-C₆ alkyl;

R₂ is H or C₁-C₆ alkyl;

R₃ is selected from the group consisting of H, C₁-C₆ alkyl, —OH,C₁-C₆alkoxy, —CO₂H, or —CONR′R′, wherein R′ for each occurrence isindependently selected from H, C₁-C₆ alkyl or a nitrogen protectinggroup; and

X is H, X′, —C₁-C₆ alkylene-X′, or —C₁-C₆ alkylene-C(O)—X′, wherein X′is selected from the group consisting of:

(i) C₃-C₆ cycloalkyl;

(ii) heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 ofthe ring atoms are independently selected from the group consisting ofN, NH, N(C1-C3 alkyl), O, and S;

(iii) phenyl; and

(iv) heteroaryl including from 5 to 6 ring atoms wherein 1, 2, or 3 ofthe ring atoms are independently selected from the group consisting ofN, NH, N(C1-C3 alkyl), O, and S;

wherein X′ is optionally substituted by one, two or three substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁-C₆ alkyl and C₁-C₆ alkoxy.

In certain embodiments, R is C₁-C₂alkyl. In some embodiments, R ismethyl. In other embodiments, R is H.

In certain embodiments, R₁ is H.

In other embodiments, R2 is H.

In some embodiments, R₃ is —CONR′R′. In certain embodiments R′ for eachoccurrence is independently selected from H and a nitrogen protectinggroup. For example, R′ for each occurrence can be H, and R₃ is —C(O)NH₂.As another example, one R′ is H, and the other is a nitrogen protectinggroup (e.g., as defined anywhere herein, e.g., pare-methoxyphenyl(PMP)).

In some embodiments, X is H or —C₁-C₆ alkylene-C(O)—X′. In certainembodiments, X is H. In other embodiments, X is —C₁-C₆ alkylene-C(O)—X′(e.g., —C₁-C₂ alkylene-C(O)—X′ or —CH₂-C(O)—X′). In certain embodiments,X′ is heterocyclyl including from 3 to 6 (e.g., 5-6 or 5) ring atomswherein 1, 2, or 3 of the ring atoms are independently selected from thegroup consisting of N, NH, N(C1-C3 alkyl), O, and S (e.g., N, NH,N(C1-C3 alkyl; e.g., in which the nitrogen atom is attached to C(O)). Incertain embodiments, X is

Embodiments in which X is H or —C₁-C₆ alkylene-C(O)—X′ can include oneor more of the following features: R is H or methyl; R₁ is II; R₂ is H;R₃ is —CONR′R′ (as defined anywhere herein, e.g., C(O)NH₂); R_(b) is H.

In some embodiments, X is X′ or —C₁-C₆ alkylene-X′. In certainembodiments. X is X′ . In other embodiments, X is —C₁-C₆ alkylene-X′(e.g., —C₁-C₂ alkylene-X′ or CH₂-X′). In certain of these embodiments,X′ is phenyl that is optionally substituted with halogen, hydroxyl,C₁-C₆ alkyl or C₁-C₆ alkoxy (e.g., X′ is para-methoxyphenyl (PMP)).Embodiments in which X is X′ or —C₁-C₆ alkylene-X′ can include one ormore of the following features: R is H or methyl; R₁ is H; R₂ is H; R₃is —CONR′R′ (as defined anywhere herein, e.g., —C(O)NH₂); R_(b), is H.

In another aspect, disclosed compounds include those represented by theformula:

and pharmaceutically acceptable salts, stereoisomers, and N-oxidesthereof, wherein

R_(b) is selected from the group consisting of H, halogen, hydroxyl,cyano and C₁-C₆ alkyl;

R is H or methyl:

R₁ is H or methyl;

R₂ is H or methyl;

R₃ is selected from the group consisting of H, C₁-C₆ alkyl, —OH, C₁-C₆alkoxy, —CO₂H, or —CONR′R′, wherein R′ for each occurrence is selectedfrom H, C₁-C₆ alkyl or a nitrogen protecting group; and

X is H or —C₁-C₆alkylene-C(O)—NR_(c)R^(d);

R^(c) and R^(d), together with the nitrogen to which they are attached,form a 4-6 membered heterocyclic which may have an additional heteroatomselected from O, S, or N; wherein the 4-6 membered heterocyclic ring mayoptionally be substituted by one or more substituents selected from thegroup consisting of halogen, cyano, oxo, and C_(l-6)alkyl.

In some embodiments, a disclosed compound includes any of thosedelineated in Table 1 and/or the Examples, e.g., one having the formula:

The compounds of the present disclosure and formulations thereof mayhave a plurality of chiral centers. Each chiral center may beindependently R, S, or any mixture of R and S. For example, in someembodiments, a chiral center may have an R:S ratio of between about100:0 and about 50:50, between about 100:0 and about 75:25, betweenabout 100:0 and about 85:15, between about 100:0 and about 90:10,between about 100:0 and about 95:5. between about 100:0 and about 98:2,between about 100:0 and about 99:1, between about 0:100 and 50:50,between about 0:100 and about 25:75, between about 0:100 and about15:85, between about 0:100 and about 10:90, between about 0:100 andabout 5:95, between about 0:100 and about 2:98, between about 0:100 andabout 1:99, between about 75:25 and 25:75, and about 50:50. Formulationsof the disclosed compounds comprising a greater ratio of one or moreisomers (i.e., R and/or S) may possess enhanced therapeuticcharacteristic relative to racemic formulations of a disclosed compoundsor mixture of compounds.

Disclosed compounds may provide for efficient cation channel opening atthe NMDA receptor, e.g. may bind or associate with the glutamate site ofthe NMDA receptor to assist in opening the cation channel. The disclosedcompounds may be used to regulate (turn on or turn off) the NMDAreceptor through action as an agonist.

The compounds as described herein may be glycine site NMDA receptorpartial agonists. A partial agonist as used in this context will beunderstood to mean that at a low concentration, the analog acts as anagonist and at a high concentration, the analog acts as an antagonist.Glycine binding is not inhibited by glutamate or by competitiveinhibitors of glutamate, and also does not bind at the same site asglutamate on the NMDA receptor. A second and separate binding site forglycine exists at the NMDA receptor. The ligand-gated ion channel of theNMDA receptor is, thus, under the control of at least these two distinctallosteric sites. Disclosed compounds may be capable of binding orassociating with the glycine binding site of the NMDA receptor. In someembodiments, disclosed compounds may possess a potency that is 10-foldor greater than the activity of existing NMDA receptor glycine sitepartial agonists.

The disclosed compounds may exhibit a high therapeutic index. Thetherapeutic index, as used herein, refers to the ratio of the dose thatproduces a toxicity in 50% of the population (i.e., TD₅₀) to the minimumeffective dose for 50% of the population (i.e., ED₅₀). Thus, thetherapeutic index =(TD₅₀):(ED₅₀). In some embodiments, a disclosedcompound may have a therapeutic index of at least about 10:1, at leastabout 50:1, at least about 100:1, at least about 200:1, at least about500:1, or at least about 1000:1.

Compositions

In other aspects, formulations and compositions comprising the disclosedcompounds and optionally a pharmaceutically acceptable excipient areprovided. In some embodiments, a contemplated formulation comprises aracemic mixture of one or more of the disclosed compounds.

Contemplated formulations may be prepared in any of a variety of formsfor use. By way of example, and not limitation, the compounds may beprepared in a formulation suitable for oral administration, subcutaneousinjection, or other methods for administering an active agent to ananimal known in the pharmaceutical arts.

Amounts of a disclosed compound as described herein in a formulation mayvary according to factors such as the disease state, age, sex, andweight of the individual. Dosage regimens may be adjusted to provide theoptimum therapeutic response. For example, a single bolus may beadministered, several divided doses may be administered over time or thedose may be proportionally reduced or increased as indicated by theexigencies of the therapeutic situation. It is especially advantageousto formulate parenteral compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suited as unitary dosages for themammalian subjects to be treated; each unit containing a predeterminedquantity of active compound calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier.

The specification for the dosage unit forms of the invention aredictated by and directly dependent on (a) the unique characteristics ofthe compound selected and the particular therapeutic effect to beachieved, and (b) the limitations inherent in the art of compoundingsuch an active compound for the treatment of sensitivity in individuals.

Therapeutic compositions typically must be sterile and stable under theconditions of manufacture and storage. The composition can be formulatedas a solution, microemulsion, liposome, or other ordered structuresuitable to high drug concentration. The carrier can be a solvent ordispersion medium containing, for example, water, ethanol, polyol (forexample, glycerol, propylene glycol, and liquid polyethylene glycol, andthe like), and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionand by the use of surfactants, In many cases, it will be preferable toinclude isotonic agents, for example, sugars, polyalcohols such asmannitol, sorbitol, or sodium chloride in the composition. Prolongedabsorption of the injectable compositions can be brought about byincluding in the composition an agent which delays absorption, forexample, monostearate salts and gelatin.

The compounds can be administered in a time release formulation, forexample in a composition which includes a slow release polymer. Thecompounds can be prepared with carriers that will protect the compoundagainst rapid release, such as a controlled release formulation,including implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers(PLG). Many methods for the preparation of such formulations aregenerally known to those skilled in the art.

Sterile injectable solutions can be prepared by incorporating thecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze-drying which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

In accordance with an alternative aspect of the invention, a compoundmay be formulated with one or more additional compounds that enhance thesolubility of the compound.

Methods

Methods for treating a condition in a patient in need thereof byadministering a therapeutically effective dose of a compound describedherein are provided. In some embodiments, the condition may be a mentalcondition. For example, a mental illness may be treated. In anotheraspect, a nervous system condition may be treated. For example, acondition that affects the central nervous system, the peripheralnervous system, and/or the eye may be treated. In some embodiments,neurodegenerative diseases may be treated.

In some embodiments, the methods include administering a compound totreat patients suffering from autism, anxiety, depression, bipolardisorder, attention deficit disorder, attention deficit hyperactivitydisorder (ADHD), schizophrenia, a psychotic disorder, a psychoticsymptom, social withdrawal, obsessive-compulsive disorder (OCD), phobia,post-traumatic stress syndrome, a behavior disorder, an impulse controldisorder, a substance abuse disorder (e.g., a withdrawal symptom, opiateaddiction, nicotine addiction, and ethanol addition), a sleep disorder,a memory disorder (e.g., a deficit, loss, or reduced ability to make newmemories), a learning disorder, urinary incontinence, multiple systematrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down'ssyndrome, fragile X syndrome, tuberous sclerosis,olivio-ponto-cerebellar atrophy, cerebral palsy, drug-induced opticneuritis, ischemic retinopathy, diabetic retinopathy, glaucoma,dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea,spasticity, myoclonus, muscle spasm, Tourette's syndrome, epilepsy,cerebral ischemia, stroke, a brain tumor, traumatic brain injury,cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy,acute neuropathic pain, and chronic neuropathic pain,

In some embodiments, methods of treating a memory disorder associatedwith aging, schizophrenia, special learning disorders, seizures,post-stroke convulsions, brain ischemia, hypoglycemia, cardiac arrest,epilepsy, migraine, AIDS dementia, Huntington's chorea, Parkinson'sdisease, early stage Alzheimer's disease, and Alzheimer's disease arecontemplated.

In certain embodiments, methods for treating schizophrenia are provided.For example, paranoid type schizophrenia, disorganized typeschizophrenia (i.e., hebephrenic schizophrenia), catatonic typeschizophrenia, undifferentiated type schizophrenia, residual typeschizophrenia, post-schizophrenic depression, and simple schizophreniamay be treated using the methods and compositions contemplated herein.Psychotic disorders such as schizoaffective disorders, delusionaldisorders, brief psychotic disorders, shared psychotic disorders, andpsychotic disorders with delusions or hallucinations may also be treatedusing the compositions contemplated herein.

Paranoid schizophrenia may be characterized where delusions or auditoryhallucinations are present, but thought disorder, disorganized behavior,or affective flattening are not. Delusions may be persecutory and/orgrandiose, but in addition to these, other themes such as jealousy,religiosity, or somatization may also be present. Disorganized typeschizophrenia may be characterized where thought disorder and flataffect are present together. Catatonic type schizophrenia may becharacterized where the patient may be almost immobile or exhibitagitated, purposeless movement. Symptoms can include catatonic stuporand waxy flexibility. Undifferentiated type schizophrenia may becharacterized where psychotic symptoms are present but the criteria forparanoid, disorganized, or catatonic types have not been met. Residualtype schizophrenia may be characterized where positive symptoms arepresent at a low intensity only. Post-schizophrenic depression may becharacterized where a depressive episode arises in the aftermath of aschizophrenic illness where some low-level schizophrenic symptoms maystill be present. Simple schizophrenia may be characterized by insidiousand progressive development of prominent negative symptoms with nohistory of psychotic episodes.

In some embodiments, methods are provided for treating psychoticsymptoms that may be present in other mental disorders, including, butnot limited to, bipolar disorder, borderline personality disorder, drugintoxication, and drug-induced psychosis. In another embodiment, methodsfor treating delusions (e.g., “non-bizarre”) that may be present in, forexample, delusional disorder are provided.

Also provided are methods for treating social withdrawal in conditionsincluding, but not limited to, social anxiety disorder, avoidantpersonality disorder, and schizotypal personality disorder.

In some embodiments, methods are provided for treating neuropathic pain.The neuropathic pain may be acute or chronic. In some cases, theneuropathic pain may be associated with a condition such as herpes, HIV,traumatic nerve injury, stroke, post-ischemia, fibromyalgia, reflexsympathetic dystrophy, complex regional pain syndrome, spinal cordinjury, sciatica, phantom limb pain, diabetic neuropathy, and cancerchemotherapeutic-induced neuropathic pain. Methods for enhancing painrelief and for providing analgesia to a patient are also contemplated.

Further contemplated methods include a method of treating autism and/oran autism spectrum disorder in a patient need thereof, comprisingadministering an effective amount of a compound to the patient. In anembodiment, a method for reducing the symptoms of autism in a patient inneed thereof is contemplated, comprising administering an effectiveamount of a disclosed compound to the patient. For example, uponadministration, the compound may decrease the incidence of one or moresymptoms of autism such as eye contact avoidance, failure to socialize,attention deficit, poor mood, hyperactivity, abnormal sound sensitivity,inappropriate speech, disrupted sleep, and perseveration. Such decreasedincidence may be measured relative to the incidence in the untreatedindividual or an untreated individual(s).

Also provided herein is a method of modulating an autism target geneexpression in a cell comprising contacting a cell with an effectiveamount of a compound described herein. The autism gene expression may befor example, selected from ABAT, APOE, CHRNA4, GABRA5, GFAP, GRIN2A,PDYN, and PENK. In another embodiment, a method of modulating synapticplasticity in a patient suffering from a synaptic plasticity relateddisorder is provided, comprising administering to the patient aneffective amount of a compound.

In another embodiment, a method of treating Alzheimer's disease, ore.g., treatment of memory loss that e.g., accompanies early stageAlzheimer's disease, in a patient in need thereof is provided,comprising administering a compound. Also provided herein is a method ofmodulating an Alzheimer's amyloid protein (e.g., beta amyloid peptide,e.g. the isoform Aβ₁₋₄₂), in-vitro or in-vivo (e.g. in a cell)comprising contacting the protein with an effective amount of a compoundis disclosed. For example, in some embodiments, a compound may block theability of such amyloid protein to inhibit long-term potentiation inhippocampal slices as well as apoptotic neuronal cell death. In someembodiments, a disclosed compound may provide neuroprotective propertiesto a Alzheimer's patient in need thereof, for example, may provide atherapeutic effect on later stage Alzheimer's—associated neuronal celldeath.

In a further embodiment, a method of treating depression comprisingadministering a compound described herein is provided. In someembodiments, the treatment may relieve depression or a symptom ofdepression without affecting behavior or motor coordination and withoutinducing or promoting seizure activity. Exemplary depression conditionsthat are expected to be treated according to this aspect of theinvention include, but are not limited to, major depressive disorder,dysthymic disorder, psychotic depression, postpartum depression,premenstrual syndrome, premenstrual dysphoric disorder, seasonalaffective disorder (SAD), bipolar disorder (or manic depressivedisorder), mood disorder, and depressions caused by chronic medicalconditions such as cancer or chronic pain, chemotherapy, chronic stress,and post traumatic stress disorders. In addition, patients sufferingfrom any form of depression often experience anxiety. Various symptomsassociated with anxiety include fear, panic, heart palpitations,shortness of breath, fatigue, nausea, and headaches among others,Anxiety or any of the symptoms thereof may be treated by administering acompound as described herein.

Also provided herein are methods of treating a condition intreatment-resistant patients, e.g., patients suffering front a mental orcentral nervous system condition that does riot, and/or has not,responded to adequate courses of at least one, or at least two, othercompounds or therapeutics. For example, provided herein is a method oftreating depression in a treatment resistant patient, comprising a)optionally identifying the patient as treatment resistant and b)administering an effective dose of a compound to said patient.

In some embodiments, a compound described herein may be used for acutecare of a patient. For example, a compound may be administered to apatient to treat a particular episode (e.g., a severe episode) of acondition contemplated herein.

Also contemplated herein are combination therapies comprising a compoundin combination with one or more other active agents. For example, acompound may be combined with one or more antidepressants, such astricyclic antidepressants, MAO-I's, SSRI's, and double and triple uptakeinhibitors and/or anxiolytic drugs. Exemplary drugs that may be used incombination with a compound include Anafranil, Adapin, Aventyl, Elavil,Norpramin, Painelor, Pertofrane, Sinequan, Surmontil, Tofranil,Vivactil, Parnate, Nardil, Marplan, Celexa, Lexapro, Luvox, Paxil,Prozac, Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel(trazodone), and Ludiomill. In another example, a compound may becombined with an antipsychotic medication. Non-limiting examples ofantipsychotics include butyrophenones, phenothiazines, thioxanthenes,clozapine, olanzapine, risperidone, quetiapine, ziprasidone,amisulpride, asenapine, paliperidone, iloperidone, zotepine, sertindole,lurasidone, and aripiprazole. It should be understood that combinationsof a compound and one or more of the above therapeutics may be used fortreatment of any suitable condition and are not limited to use asantidepressants or antipsychotics.

EXAMPLES

The following examples are provided for illustrative purposes only, andare not intended to limit the scope of the disclosure.

Table 1 below shows some exemplary compounds of the disclosure andprovides physiochemical characteristics of the compounds.

TABLE 1 Molecular Weight Compound Structure (Da) cLogP tPSA Compound X

213 −2.20 95.7 Compound Y

338 −2.04 107.2 S5-C5

439.5042 2.02408 91.34 S5-C12

423.5048 2.24827 82.11 S5-C11

303.3562 −0.251883 86.87 S5-C4

425.4776 1.6075 91.34 S5-C7

425.4776 1.6075 91.34

Example 1 Synthesis of Compound Y

Synthesis of 1-tert-butyl 2-methyl2-(benzyloxymethyl)pyrrolidine-1,2-dicarboxylate (1)

In a 500 mL 2-neck RBF Boc-Pro-OMe (5 g, 21.83 moles) was dissolved inTHF (50 mL) and charged with nitrogen. The resulting reaction mixturewas cooled to −45° C. LiHMDS (26 mL, 26.20 mmol) was added drop wise tothe reaction mixture at −45° C. The resulting reaction mixture wasstirred at −45° C. for 1 h. Benzyl chloromethyl ether (3.14 mL, 26.20moles) was added drop wise to the reaction mass at −45° C. The resultingreaction mixture was stirred for 1 hr at −45° C. and allowed to rt.After the completion of the reaction, reaction mixture was cooled to 0°C. and quenched with saturated NH₁Cl (20 mL) and extracted with EtOAc(2×25 mL). The combined organic extracts were washed with saturatedbrine solution. (2×25 mL) and dried over anhydrous Na₂SO₄. The organiclayer was concentrated under reduced pressure. The obtained crude (6.8g) material 1 was used for next step without further purification.

Synthesis of2-(benzyloxymethyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid(2)

In a 200 mL round bottom flask, 1 (7 g, 20. 05 mmol) was taken in a MeOH(50 mL). At 0° C. added 1 M, 5 eq of NaOH solution and stirred, allowedto reach the room temperature and refluxed for 3 hr. After completion ofthe reaction, the volatiles were evaporated and added water (50 mL). Theaqueous layer was acidified using 5% citric acid solution and extractedwith ethyl acetate (3×25 mL). The combined organic layer was washed withbrine and dried over Na₂SO₄. The organic layer was evaporated underreduced pressure to give the analytically pure2-(benzyloxymethyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid(2) (4.5 g, 67% yield).

Synthesis of tert-butyl2-(benzyloxymethyl)-2-(2-oxo-2-(pyrrolidin-1-yl)ethylcarbamoyl)pyrrolidine-1-carboxylate(3):

In a 2-neck 25 mL RBF with guard tube, 2 (3.5 g, 10.44 mmol) wasdissolved in THF (30 mL). The reaction kept in ice-salt bath and addedNMM (3.5 mL, 31.34 mmol), ECF (1.2 mL, 12.53 mmol). After 10 min ofstirring, a solution of 2-amino-1-(pyrrolidin-1-yl)ethanone (3.03 g,12.53 mmoles) in THF (20 mL) was added. The resulting reaction mixturewas stirred at rt for 16 h. After the completion of the reaction, thereaction mixture was concentrated under reduced pressure and dilutedwith cold water (20 mL) and extracted with EtOAc (2×30 mL). The combinedorganic extracts were washed with 5% citric acid solution (2×30 mL),saturated NaHCO₃ solution (20 mL), brine solution (15 mL) and dried overanhydrous Na₂SO₄. The organic layer was concentrated under reducedpressure, purified by column chromatography using 30% ethyl acetate andhexanes to give 3 (2.3 g, yield 49.5%) as colorless oil.

Synthesis of tert-butyl2-(hydroxymethyl)-2-(2-oxo-2-(pyrrolidin-1-yl)ethylcarbamoyl)pyrrolidine-1-carboxylate(4)

In a steel hydrogenation vessel, 10% Pd-C (200 mg), methanol (20 mL) and3 (1.7 g, 3.82 mmole) was charged under N₂ atmosphere. Reaction mixturewas hydrogenated (60 Psi H₂ pressure) using Parr hydrogenation at rt for12 h. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite bed and washed with methanol (20 mL). The filtrate wasconcentrated under reduced pressure to give 4 (1.3 g, yield 96%) whichwas used without purification for next step.

Synthesis of tert-butyl1-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2.5-diazaspiro[3.4]octane-5-carboxylate(5)

To a solution of 4 (1.47 g, 4.15 mmol) in THF (10 mL) at 0° C. temp wasadded TPP (2.17 g, 8.30 mmol) and DIAD (1.64 mL, 8.30 mmol). To theresulting reaction mixture was stirred at room temperature for 10 minand then sonicated for 3 hr. After completion of the reaction(disappearance of 4 monitored by TLC), volatiles were evaporated underreduced pressure. Column chromatography on silica gel eluted with 50%EtOAc in hexanes afforded 5 (900 mg, yield 64.7%) as gummy oil.

Synthesis of2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,5-diazaspiro[3.4]octan-1-one (6)

In a 50 mL RBF 5 (2 g, 5.95 mmol) was taken in a DCM (22 mL). At 0° C.;added TFA (6 mL) and stirred at ambient temperature for 1 hr, thereaction was monitored by TLC. After completion of the reaction, thevolatiles were evaporated under reduced pressure, neutralized with NH₄OHand purified by column chromatography on silica gel eluted with 5%methanol in DCM gave 6 (1.4 g, yield 98%) as gummy solid.

Synthesis of(2R,3S)-3-hydroxy-N-(4-methoxyphenyl)-2-(1-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,5-diazaspiro[3.4]octan-5-yl)butanamide(7)

In a 25 mL RBF 6 (50 mg, 0.21 mmol) was taken in a EtOH (7 mL),(2R,3S)-N-(4-methoxyphenyl)-3-methyloxirane-2-carboxamide (48 mg, 0.232mmol) and added TEA (0.05 mL, 0.27 mmol). The resulting reaction mixturewas irradiated to microwaves (1 min ×10 times). After completion of thereaction, the volatiles were evaporated under reduced pressure andpurified by prep. HPLC to afford 7 (10 mg, yield 5%) gummy oil. ¹H-NMR:(400 MHz, CDCl₃): δ9.34 (s, 1H); 7.46 (d, 2H); 6.83 (d, 2H); 4.25 (d,1H); 4.17 (d, 1H); 3.66 (d, 3H); 3.47-3.39 (m, 4H); 3.35-3.33 (m, 2H);3.13-3.09 (m, 2H); 2.33 (q, 2H); 2.16 (q, 1H);1.96 (q, 3H); 1.85 (q, 3H); 1.25 (d, 3H). HPLC: 99.66% (RT-10.93 min).

Synthesis of(2S,3R)-3-hydroxy-2-(1-oxo-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,5-diazaspiro[3.4]octan-5-yl)butanamide(Compound Y)

Iodobenzene diacetate (31.2 mg, 0.10 mmol) was dissolved in methanol (3mL). 7 (12 mg, 0.02 mmol) was dissolved in methanol (2 mL), taken up ina syringe and added to the oxidant solution over 30 min. The syringe wasrinsed with methanol (2×1 mL) and the rinses were added to the reaction.The reaction was allowed to stir for an additional 30 min and thenacidified with 1 N HCl (1 mL) and allowed to stir for 1.5 h. Thereaction mixture was washed with DCM (2×10 mL) and combined organicswere back extracted with 0.1 M HCl (1×10 mL), saturated NaHCO₃ solution(10 mL), brine solution (5 mL) and dried over anhydrous Na₂SO₄. Theorganic layer was concentrated under reduced pressure, purified bycolumn chromatography using 2% MeOH in DCM to give Compound Y (7 mg, 79yield %) as colorless oil. ¹H-NMR: (400 MHz, CDCl₃): δ7.22 (d, 1H); 6.86(d, 1H); 6,21 (d, 1H); 6.18 (d, 1H); 5.48 (s, 1H); 5.03-5.08 (m, 1H);4.37-4.21 (m, 2H); 4.10 (d, 2H); 3.90 (d, 1H); 3.71 (d, 2H); 2,59-2.54(m, 2H);2.26-2.12 (m, 2H); 1.97 (q, 3 H); 1.90 (q, 3H); 1.50 (d, 3H).

Preparation of Key Intermediates

Step I-1: Syntheses of 1-(tert-butoxycarbonyl) 4-(methoxycarbonyl)pyrrolidine-2-carboxylic acid:

To a stirred solution of Boc-Pro-OMe (20 g, 87.33 mmoles) in drytetrahydrofuran (200 mL) was added LiHMDS (113 mL, 113.5 mmoles) at −45°C. and stirred for 1 h. Carbon dioxide gas bubbled into the reaction for1 h at −45° C. After completion of the starting material, reactionmixture was poured into cold water. The aqueous layer was acidified with1N HCl at 0° C. and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine solution and dried over anhydrousNa₂SO₄ and concentrated under vacuum to give I-1 (12.4 g, yield: 49.0%)as a gummy liquid.

TLC system: 50% EtOAe-Hexane

Rf-value: 0.2

Visualization: Ninhydrine stain

Analytical data:

Mass (m/z): 174.1 (M-Boc)⁺

Step I-2: Synthesis of 1-tert-butyl 2-methyl 2-(4-methoxyphenylcarbamoyl) pyrrolidine-1, 2-dicarboxylate:

To a solution of I-1 (15.4 g, 55.59 mmoles) in dichloromethane (160 mL)was added 4-methoxy aniline (6.83 g, 55.59 mmoles) in presence of NWM(12.47 mL, 111.18 mmoles). EDC. HCl (12.93 g, 83.39 mmoles) was added tothe reaction mixture at 0° C. and allowed to stir at rt for 12 h. Afterthe completion of reaction, the reaction mixture was diluted with DCM(100 mL). The organic layer was washed with cold water, 10% aq. citricacid, 5% aq. sodium bicarbonate, brine solution and dried over anhydrousNa₂SO₄ and concentrated under vacuum to give 1-tert-butyl 2-methyl2-(4-methoxyphenyl carbamoyl) pyrrolidine-1, 2-dicarboxylate, I-2, (12.6g, yield: 60.2%) as gummy liquid.

TLC system: 50% EtOAe-Hexane

Rf-value: 0.2

Visualization: UV & Ninhydrin stain

Analytical data:

Mass (m/z): 279.2 (M-Boc)⁺

Step I-3: Synthesis of tert-butyl2-(hydroxymethyl)-2-(4-methoxypheneylcarbamoyl)pyrrolidine-1-carboxylate:

To a solution of I-2 (12 g, 31.74 mmoles) in MeOH (120 mL) was addedLithium bromide (16.56 g, 190.46 mmoles) and sodium borohydride (7.22 g,190.46 mmoles), the reaction mixture was allowed to stir for 12 h. Afterthe completion of reaction, methanol was evaporated under reducedpressure. The reaction mixture was quenched with water and extractedwith ethyl acetate (3×100 mL). The combined organic layers were washedwith brine solution and dried over anhydrous Na₂SO₄ and concentratedunder vacuum to get crude. The crude was purified by columnchromatography (100-200 mesh silica gel, 50% EtOAc in hexane) to giveI-3 (5.5 g, yield 49.7%) as white solid.

TLC system: 50% EtOAc-Hexane

Rf-value: 0.3

Visualization: UV & Ninhydrin stain

Mass (m/z): 251.1(M-Boc)

Step I-4: Synthesis of tert-butyl 2-(4-methoxyphenyl)-1-oxo-2,5-diazaspiro [3.4] octane-5-carboxylate:

To a solution of I-3 (5.5 g, 15.76 mmoles) in dry tetrahydrofuran (20were added triphenylphosphine (8.26 g, 31.51 mmoles) and DIAD (6.36 mL,31.51 mmoles). The mixture was sonicated for 3 h. After the completionof reaction, the solvent was evaporated under reduced pressure, thecrude material was purified by column chromatography (100-200 meshsilica gel, 40% EtOAc in hexane) to give of I-4 (3.64 g, yield: 70%) asgummy syrup.

TLC system: 50% EtOAc-Hexane

Rf-value: 0.3

Visualization: UV & Ninhydrin stain

Analytrical data:

Mass (m/z): 333.1(M+H)⁺

Step I-5: Synthesis of 2(4-methoxyphenyl)-2, 5-diazaspiro [3.41]octan-1-one:

To a solution of I-4 (3.64 g, 10.99 moles) in dichloromethane (30 mL)was added trifluoroacetic acid (15 mL) at 0° C. The reaction mixture waswarmed to room temperature and stirred for 2 h. After the completion ofreaction, the solvent was evaporated under reduced pressure to get crudecompound. The crude compound was dissolved in methanol (5 mL) andbasified with aqueous ammonia solution at 0° C. The crude compound waspurified by column chromatography (100-200 mesh silica gel, 5% Methanolin DCM) to give I-5 (2.04 g, yield: 80%) as a pale yellow solid.

TLC system: 100% EtOAc

Rf-value: 0.1

Visualization: UV & Ninhydrin stain

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.26 (d, 2H), 6.86 (d, 2H), 3.70 (s, 3H), 3.64(d, 1H), 3.59 (d, 1H), 3.22 (m, 1H), 3.05 (m, 1H), 2.26 (m, 1H),2.08-2.02 (m, 2H), 1.84 (m, 2H).

Step-1: Synthesis of 1-tert-butyl 2-methyl 2-(benzylcarbamoyl)pyrrolidine-1, 2-dicarboxylate:

Referring to Scheme I-2, to a stirred solution of I-1 (6.0 g, 21.58mmoles) in dichloromethane (100 mL) at rt under nitrogen atmosphere. Thereaction was cooled to −5° C. added N-methyl morpholine (4.79 mL, 43.16mmoles) and EDC. HCl (5.02 g, 32.37 mmoles). Benzyl amine (2.2 g, 21.58mmoles) was added to the reaction mixture and stirred for 12 h at rt.After the completion of reaction, the reaction mixture was concentratedunder reduced pressure to get a residue. The residue was dissolved inethyl acetate (100 mL) and washed with 10% citric acid, 5% sodiumbicarbonate, brine solution and dried over anhydrous Na₂SO₄ andconcentrated under vacuum to get crude. The obtained crude was purifiedby column chromatography (100-200 mesh silica gel, 25% EtOAc in hexane)to give 1-tert-butyl 2-methyl 2-(benzylcarbamoyl) pyrrolidine-1,2-dicarboxylate, I-6, (4.0 g, yield: 55.5%) as light yellow liquid.

TLC system: 50% EtOAc-Hexane

Rf-value: 0.4

Visualization: UV & Ninhydrin stain

Analytical data

¹H NMR (400 MHz, CDCl₃): δ8.43 (br, 1H), 7.31-7.28 (m, 5H), 4.53-4.46(m, 2H), 3.75 (s, 3H), 3.72 (t, 1H), 3.53 (d, 1H), 2.94 (t, 1H), 2.20(d, 1H), 2.03-1.92 (m, 2H), 1.63 (s, 9H).

Mass (m/z): 263.2 (M-Boc)⁺

Step-2: Synthesis of tert-butyl 2-(benzylcarbamoyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate:

To a solution of I-6 (4.0 g, 11.04 mmoles) in methanol (50 mL) was addedlithium bromide (9.61 g, 110.4 mmoles), sodium borohydride (4.2 g, 110.4mmoles) and stirred at rt for 12 h. After the completion of reaction,methanol was evaporated under reduced pressure to get crude. The crudewas quenched with water and extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine solution and dried overanhydrous Na₂SO₄ and concentrated under vacuum to get crude. The crudewas purified by column chromatography (100-200 mesh silica gel, 30%EtOAc-Hexane) to give tert-butyl 2-(benzylcarbamoyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate, I-7, (2.3 g, yield: 62.3%) as white solid.

TLC system: 50% EtOAc-Hexane

Rf-value: 0.3

Visualization: UV & phosphomolybdic acid stain

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.35-7.28 (m, 5H), 6.90 (br, s, 1H), 4.46 (m,2H), 4.03 (s, 1H), 3.88 (s, 1H), 3.62-3.56 (m, 2H), 3.49 (d, 2H), 3.42(s, 1H), 2.61 (d, 1H), 2.31 (m, 1H), 1.59 (s, 9H).

Mass (m/z): 235.2 (M-Boc)⁺

Step-3: Synthesis of tert-butyl 2-benzyl-1-oxo-2, 5-diazaspiro [3, 4]octane-5-carboxylate:

To a solution of I-7 (2.30 g, 6.88 mmoles) and triphenyl phosphine (3.61g, 13.77 mmoles) in dry tetrahydrofuran (30 mL) were stirred at rt undernitrogen atmosphere. Diisopropyl azodicarboxylate (2.78 mL, 13.77mmoles) was added to the reaction mixture at rt. The resulting reactionmixture was sonicated for 4 h. After the completion of reaction, thereaction was concentrated under reduced pressure to get crude. The crudematerial was purified by column chromatography (100-200 mesh silica gel,30% EtOAc in hexane) to give tert-butyl 2-benzyl-1-oxo-2, 5-diazaspiro[3, 4] octane-5-carboxylate, I-8, (1.74 g, yield 80%) as a pale yellowliquid.

TLC system: 50% EtOAc-Hexane

Rf-value: 0.4

Visualization: UV & phosphomolybdic acid stain

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.37-7.28 (m, 5H), 4.88 (d, 1H), 3.89 (d, 1H),3.51-3.49 (m, 2H), 3.08 (d, 114), 2.40-2.35 (m, 1H), 2.09 (d, 2H),1.9-1,91 (m, 1H), 1.78-1.74 (m, 1H), 1.46 (s, 9H).

Mass (m/z): 216.2 (M-Boc)⁺

Step-4: Synthesis of 2-benzyl-2, 5-diazaspiro [3, 4] octan-1-one:

To a solution of I-8 (700 mg, 2.21 mmoles) in dichloromethane (10 mL)was added trifluoroacetic acid (5 mL) at room temperature and stirredfor 2 h. After the completion of reaction, the reaction mixture wasconcentrated under reduced pressure and quenched with ice water. Theaqueous layer was basified with ammonia solution up to P^(H)˜10 andconcentrated under reduced pressure to get crude compound. The crudecompound was purified by column chromatography (100-200 mesh silica gel,5% Methanol in DCM) to give 2-benzyl-2, 5-diazaspiro [3, 4] octan-1-one,I-9, (400 mg, yield: 83.7%) as a pale green syrup.

TLC system: 10% Methanol-DCM

Rf-value: 0.3

Visualization: UV & phosphomolybdic acid stain

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.36-7.22 (m, 5H), 4.38 (q, 2H), 3.20-3.13 (m,3H), 3.01-2.97 (m, 1H), 2.21-2.18 (m, 1 H), 2.02-1.99 (m, 1H), 1.99-1.91(m, 1H), 1.85-1.80 (m, 1H).

Mass (m/z): 217.2 (M−H)⁻

LC-MS (% Area Method): 97.79%

Step-1: Synthesis of Ethyl 2-(2-(4-methoxyphenyl)-1-oxo-2, 5-diazaspiro[3. 4] octan-5-yl) acetate:

Referring to Scheme 1, to a solution of I-5 (160 mg, 0.698 mmoles) inacetonitrile (5 mL) was added potassium carbonate (571 mg, 4.19 mmoles)and bromo ethyl acetate (0.11 mL, 1.05 mmoles) and the resultingreaction mixture was heated to 70° C. for 12 h. After the completion ofreaction the reaction was filtered through celite bed and filtrate wasconcentrated under reduced pressure to get crude compound. The crudecompound was purified by column chromatography (100-200 mesh silica gel,40% EtOAe in hexane) to give S5-C1 (130 mg, yield 60%) as a brownliquid.

TLC system: 50% EtOAc-Hexane

Rf-value: 0.3

Visualization: UV & phosphomolybdic acid stain

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.31 (d, 2H), 7.30 (d, 2H), 6.87 (d, 2H), 4.26(q, 2H), 3.79 (s, 3H), 3.69 (s, 1H), 3.63 (m, 1H), 3.53 (d, 1H),3.36-3.34 (m, 1H), 2.88 (q, 1H), 2.40-2.34 (m, 1H), 2.26-2.4 (m, 1H),2.03-1.97 (m, 1H), 1.29-1.24 (m, 3H).

Mass (m/z): 319.2 (M−H)⁻

LC-MS (% Area Method): 90.13%

Step 2: Synthesis of ethyl2-methoxy-2-(2-(4-methoxyphenyl)-1-oxo-2,5-diazaspiro[3, 4]octan-5-yl)acetate:

A stirred solution of S5-C1 (75 mg, 0.23 mmoles) in tetrahydrofuran (2mL) at rt under nitrogen atmosphere was cooled to −40° C. LiHMDS (0.35mL, 0.35 mmoles) was added to the reaction mixture and stirred for 40min at −40° C. MOM chloride (0.075 mL, 0.46 mmoles) was added drop wiseto the reaction and stirred for 10 min at −40° C. The resulting reactionmixture was allowed to stir at rt for 12 h. After the completion ofreaction, the reaction mixture was quenched with saturated ammoniumchloride and extracted with ethyl acetate. The combined organic layerswere washed with water, brine solution and dried over anhydrous Na₂SO₄and concentrated under vacuum to obtain the crude product which waspurified by column chromatography (100-200 mesh silica gel, 25% EtOAc inhexane) to give S5-C2 (10 mg, yield: 35%) as an light yellow liquid.

TLC system: 50% EtOAc-Hexane

Rf-value: 0.4

Visualization: UV & Ninhydrin

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.30 (d, 2H), 6.86 (d, 2H), 4.19-4.16 (m, 2H),3.88 (m, 1H), 3.77 (s, 3H), 3.74-3.71 (m, 3H), 3.64 (m, 1H), 3.52 (m,1H), 3.33 (m, 2H), 3.28-3.21 (m, 1H), 3.11-3.07 (m, 1H), 2.38-2.30 (m,1H), 2.14-2.09 (m, 1H), 1.99-1.82 (m, 2H), 1.22 (3H).

Mass (m/z): 362.7 (M)⁺

LC-MS (% Area Method): 85.8% (RT 10.7 min)

Step 3

To a solution of S5-C2 (100 mg, 0.276 mmoles) in dry DCM (2 mL) wasadded boron tribromide (1.3 mL) at −78° C. and stirring continued for 4h. After the completion of starting compound, the reaction was quenchedwith aq, sat. sodium bicarbonate and extracted with DCM, (2×10 mL). Thecombined organic layers were washed with brine solution and dried overanhydrous Na₂SO₄ and concentrated under vacuum to get crude. The crudereaction mixture was purified by column chromatography (100-200 meshsilica gel, 40% EtOAc in hexane) to give S5-C3 (20 mg, yield: 9.6%) as acolorless syrup.

TLC system: 50% EtOAc-Hexane. Rf-value: 0.3

Visualization: UV

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.35 (d, 2H, J=8.8 Hz), 6.89 (d, 2H, J=8.8Hz), 4.19 (m, 2H), 3.82 (m, 1H), 3.72-3.89 (m, 5H), 3.67 (d, 1H), 3.19(m, 1H), 2.98 (m, 1H), 2.45 (m, 1H), 2.20 (m, 1H), 2.01 (m, 2H), 1.29(m, 2H), 1.32 (t, 3H).

Mass (m/z): 348.7 (M)⁺

LC-MS (% Area Method): 90% (RT: 8.8 min and 9.4 min; diastereomers)

Step 4:

To a solution of S5-C3 (40 mg, 0.11 mmoles) in ethanol (2 mL) aq.ammonia (2 mL) was added at 0° C., and stirred for 12 h at rt. After thecompletion of starting material, the reaction mixture was diluted withDCM (25 mL) and washed with water (2×15 mL). The combined organic layerswere washed with brine solution and dried over anhydrous Na₂SO₄. Thesolvent was evaporated under vacuum to obtain crude product, which waspurified by column chromatography (100-200 mesh silica gel, 2% MeOH inDCM) to give S5-C4 (12 mg, yield 33%) as a colorless gummy solid.

TLC system: 10% MeOH in DCM. Rf-value: 0.2

Visualization: UV

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.63 (br s, 1H), 7.18 (d, 2H), 6.90 (d, 2H),5.80 (s, 1 H), 4.23 (m, 1 H), 3.98 (m, 2H), 3.86 (m, 2H), 3.80 (s, 3H),3.62 (m, 1H), 3.21 (m, 11H), 2.72 (m, 1H), 2.40 (m, 1H), 1.80 (m, 2H),1.68 (m, 1H).

Mass (m/z): 319.7 (M)⁺

Step-1: Synthesis of2-hydroxy-N-(4-methoxyphenyl)-3-(2-(4-methoxyphenyl)-1-oxo-2,5-diazaspiro[3.4]octan-5-yl)propionamide&3-hydroxy-N-(4-methoxyphenyl)-2-(2-(4-methoxyphenyl)-1-oxo-2,5-diazaspiro[3,4]octan-5-yl)propionamide:

Referring to Scheme 2, to a mixture of I-5 (300 mg, 1.29 mmoles),(R)—N-(4-methoxyphenyl)oxirane-2-carboxamide (275 mg, 1.42 mmoles) andtriethyl amine (0.3 mL, 5.16 mmoles) in ethanol (30 mL) was heated usingmicrowave for 10 min at 800 W (1 min ×10 times). After the completion ofreaction, the reaction was concentrated under reduced pressure to getcrude. The crude material was purified by Prep HPLC to give S5-C7 (70mg, 30%) and S5-C7′ (75 mg, 33%) as a brown syrup.

TLC system: 10% Methanol-DCM

Rf-value: 0.4

Visualization: UV & phosphomolybdic acid stain

Analytical data: C-5:

¹H NMR (400 MHz, CDCl₃): δ8.85 (s, 1H), 7.51 (d, 2H), 7.30 (d, 2H), 6.86(m, 4H), 4.18 (t, 1H), 3.80 (s, 1H), 3.78 (s, 6H), 3.74 (d, 1H), 3.54(d, 1 H), 3.21 (m, 1H), 3.19-3.16 (m, 2H), 2.90 (m, 1H), 2.42 (q, 1H),2.20-2.17 (m, 1H), 2.03-1.95 (m, 1H), 1.92 (m, 1H).

Mass (m/z): 425.5 (M)⁺

HPLC (% Area Method): 93.7%

Analytical data: C-5′:

¹H NMR (400 MHz, CDCl₃): δ8.95 (s, 1H), 7.45 (d, 2H), 7.30 (d, 2H),6.92-6.85 (m, 4H), 4.80 (dd, 1H), 4.16 (m, 2H), 3.96 (s, 1 H), 3.88 (dd,1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.48 (q, 1H), 3.36 (q, 1H), 2.68-2.58(m, 1H), 2.56-2.47 (m, 1H), 2.42-2.30 (m, 1H), 2.18-2,11 (m, 1H).

Mass (m/z): 425.6 (M)⁻

HPLC (% Area Method): 98.25%

Step 2: Synthesis of 3-hydroxy-2-(1-oxo-2, 5-diazaspiro [3,4]octan-5-yl) propionamide:

To a solution of S5-C7 (30 mg, 0.070 mmoles) in acetonitrile and water(3 mL, 2:1) was added cerric ammonium nitrate (154 mg, 0.352 mmoles) at0° C. and stirred for another 3 h at 0° C. After completion of reaction,acetonitrile was evaporated under reduced pressure and diluted withwater (15 mL). The aqueous layer was washed with ethyl acetate to removeimpurities. Evaporation of the aq. layer under reduced pressure gave thecrude product which was purified by column chromatography (100-200 meshsilica gel, 2-8% Methanol in DCM) to give S5-C6 (10 mg, yield: 66%) as alight yellow gummy solid.

TLC system: 100% EtOAc

Rf-value: 0.1

Visualization: Phosphomolybdic acid stain

Analytical data:

Mass (m/z): 214.7 (M−H)⁺

¹H NMR (400 MHz, D₂O): ** Broad peak shapes were observed in D₂O

Step-1 Synthesis of3-hydroxy-N-(4-methoxyphenyl)-2-(2-(4-methoxyphenyl)-1-oxo-2,5-diazaspiro [3, 4] octan-5-yl) butanamide:

Referring to Scheme 3, to a mixture of I-5 (100 mg, 0.431 mmoles),epoxide (98 mg, 0.474) and triethyl amine (0.1 ml 1.72 mmoles) isethanol (10 mL) was heated using microwave for 10 min at 800 W (1 min×10 times). After the completion of reaction, the reaction wasconcentrated reduced pressure to get crude. The crude was purified byPrep HPLC to give3-hydroxy-N-(4-methoxyphenyl)-2-(2-(4-methoxyphenyl)-1-oxo-2,5-diazaspiro[3,4]octan-5-yl)butanamide,S5-C5, (25 mg, yield: 13.4%) as a light yellow gummy solid.

TLC system: 50% EtOAc-Hexane. Rf-value: 0.3

Visualization: UV

Analytical data:

¹H NMR(400 MHz, CDCl₃): δ9.30 (s, 1H), 7.44 (d, 2H), 7.27 (d, 2H), 6.87(d, 4H), 4.15 (m, 1H), 3.80 (s, 6H), 3.79 (s, 1H), 3.61 (s, 1H), 3.37(m, 1H), 3.26 (q, 1H), 3.02 (m, 1H), 2.43 (q, 1H), 2.23 (m, 2H),2.07-2.05 (m, 1H), 2.02-1.96 (m, 1H), 1.37 (d, 3H).

Mass (m/z): 439.5 (M)⁺

LC-MS (% Area Method): 91.30%

Step 1

Synthesis of C5-C8:

Referring to Scheme 4, anhydrous K₂CO₃ (2.3 g, 16.6 mmoles) was added toa stirred solution of I-9 (600 mg, 2.77 mmoles) and ethylbromoacetate(0.46 mL, 4.16 mmoles) in acetonitrile (10 mL). The resulting mixturewas heated at 65° C. for 12 h, then cooled to ambient temperature andfiltered. The residue was washed with acetonitrile (2×10 mL), andcombined of organic layers evaporated in vacuo. The residue wasdissolved in EtOAc (25 mL), the solution was washed was washed withwater (2×15 mL), brine, dried over Na₂SO₄, filtered, volatiles wasevaporated in vacuo, and the residue subjected to the columnchromatography on silica gel (100-200 mesh) using 30% EtOAc in hexanesas eluant to afford S5-C8 (640 mg, yield 76%) pale yellow syrup.

TLC system: 50% EtOAc in Hexanes

Rf-value: 0.4

Visualization: UV & minhydrin stain

LNB No: COS-13-A006-45

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.37 (m, 3H), 7.23 (m, 2H), 4.37 (s, 2H), 4.17(q, 2H), 3.45 (s, 3.28 m, 1H), 3.22 (d, 1H), 3.15 (d, 1H), 2.84 (q, 1H),2.28-2.26 (m, 1H), 2.09 (m, 1H), 1.96-1.89 (m, 2H), 1.24 (t, 3H).

Mass (m/z): 302.7 (M)⁺

Step 2 Synthesis of S5-C9:

To a solution of S5-C8 (100 mg, 0.331 mmoles) in dry tetrahydrofuran (5mL) cooled to −78° C.; was added LiHNIDS (0.66 mL)and stirred for 45min. MOM-C1 (0.018 mL) was added dropwise to the reaction mixture andstirred for 2 h at −78° C. and, 12 h at room temperature. After thecompletion of reaction, the reaction mixture was quenched with satammonium chloride. The aqueous layer was extracted with ethyl acetate(2×10 mL). The combined organic layers were washed with brine solutionand dried over anhydrous Na₂SO₄ and concentrated under vacuum to getcrude product. Which was purified by column chromatography (100-200 meshsilica gel, 30% EtOAc in hexane) to give S5-C9 (20 mg, yield: 22%) ascolorless syrup.

TLC system: 50% EtOAc-Hexane. Rf-value: 0.45

Visualization: UV

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.36-7.25 (m, 5H), 4.40-4.39 (d, 2H, J=4.8Hz), 4.21-4.19 (d, 2H, J=3.84 (m, 1H), 3,76 (m, 1H), 3.64 (m, 1H), 3.36(s, 3H), 3.29 (m, 1H), 3.19 (m, 1H), 3.18-3.11 (m, 1H), 3.02 (m, 1H),2.32 (m, 1H), 2.06 (m, 1H), 1.88-1.75 (m, 2H), 1.22 (t, 3H, J=8 Hz)

Mass (m/z): 346.7 (M)⁺

LC-MS (% Area Method): 89.31% (RT: 10.4 min)

Step 3

To a solution of S5-C9 (60 mg, 0.173 mmoles) in dry DCM (2 mL) was addedboron tribromide (1.72 mL) at −78° C. and stirred at −78° C. for 12 h.After the completion of reaction, the reaction was quenched with sat.sodium bicarbonate and extracted with DCM (2×10 mL). The combinedorganic layers were washed with brine solution and dried over anhydrousNa₂SO₄ and concentrated under vacuum to get crude. The crude reactionmixture was purified by column chromatography (100-200 mesh silica gel,50% EtOAc in hexane) to give S5-C10 (13 mg, yield: 23%) as colorlesssyrup.

TLC system: 50% EtOAc-Hexane. Rf-value: 0.3

Visualization: UV

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.37-7.24 (m,10 H), 4.44-4.40 (m, 2H), 4.29(m, 2H), 4.21-4.19 (m, 2H), 4.08 (m, 2H), 3.89 (n, 1H), 3.85 , (m, 1H),3.69 (m, 1H), 3.65-3.63 (m, 3H), 3.36-3.34 (m, 2H), 3.22-3.21 (m, 1H),3.14-3.10 (m, 5H), 3.09 (m, 1H), 2.39 (m, 2H), 2.12-1.75 (m, 5H),1.99-1.89 (m, 2H), 1.31-1.27 (m, 3H, J=16Hz), 1.22-1.19 (t, 3H, J=12Hz).

Mass (m/z): 332.70 (M)⁺

LC-MS (% Area Method): 96.2.1% (RT: 8.6 min and 9.4 min)

Step 4

To a solution of S5-C10 (100 mg, 0.301 mmoles) in ethanol (4 mL) andadded at ammonia was added and stirred for 12 h at rt. After thecompletion of reaction, the reaction was diluted with DCM (25 mL) andwashed with water (2×15 mL). The combined organic layers were washedwith brine solution and dried over anhydrous Na₂SO₄ and concentratedunder vacuum to get the crude product, which was purified by columnchromatography (100-200 mesh silica gel, 2% MeOH in DCM) to give S5-C11(60 mg, 66%) as colorless syrup.

TLC system: 10% MeOH in DCM. Rf-value: 0.4

Visualization: UV

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ7.53 (br s, 1H), 7.35-7.28 (m, 5H), 5.51 (brs, 1H), 4.72-4.68 (d, 1H, J =16 Hz), 4.48-4.45 (d, 1H, J=12 Hz), 4.14(m, 1H), 3.87 (m, 1H), 3.56-3.52 (d, 1H, J=16 Hz), 3.47 (m, 1H),3.41-3.37 (d, 1H, J=16 Hz), 3.20 (br s, 1H), 3.06 (m, 1H), 2.50 (m, 1H),2.15 (m, 1H), 1.59-1.56 (m, 2H), 1.25 (m, 1H).

Mass (m/z): 303.7 (M)⁺

Step-1 Synthesis of2-(2-benzyl-1-oxo-2,5-diazaspiro[3,4]octan-5-yl)-3-hydroxy-N-(4-methoxyphenyl)butanamide:

Referring to Scheme 5, to a mixture of I-9 (200 mg, 0.925 mmoles),epoxide (175 mg, 1.01) and triethyl amine (0.43 mL) in ethanol (10 mL)was irradiated to micro waves for 10-12 min at 800 W min ×12 times).After the completion of reaction, the reaction was concentrated reducedpressure to get crude mixture. The crude was purified by columnchromatography (100-200 mesh silica gel, 60-70% EtOAc in Hexane) to give2-(2-benzyl-1-oxo-2,5-diazaspiro[3,4]octan-5-yl)-3-hydroxy-N-(4-methoxyphenyl)butanamide,S5-C12, (15 mg, 4%) as a colorless gummy syrup.

TLC system: EtOAc Rf-value: 0.4

Visualization: UV

Analytical data:

¹H NMR (400 MHz, CDCl₃): δ9.33 (s, 1H), 7.40 (t, 2H), 7.35-7.29 (m, 3H),7.19 (d, 2H), 6.85 (d, 2H), 4.42 (d, 1H), 4.31 (d, 1H), 4.10 (d, 1H),3.78 (s, 3H), 3.27 (d, 1H), 3.23-3.15 (m, 2H), 3.08 (d, 1H), 2.90 (d,1H), 2.36-2.30 (m, 1H), 2.09-2.03 (m, 1H), 1.99 (m, 2H), 1.87-1.83 (m,1H), 1.31 (d, 3H).

Mass (m/z): 424.30 (M+H)⁺

LC-MS (% Area Method): 95.31% (RT: 9.9 min)

Example 2 [³H] MK-801 Binding Assay

Methods

Assays were conducted as described in Moskal et al. (Moskal, J. R., Kuo,A. G., Weiss, C., Wood, P. L., O′Connor Hanson, A., Kelso, S., Harris,R. B., Disterhoft, S. F., 2005. GLYX-13: a monoclonal antibody-derivedpeptide that acts as an N-methyl-D-aspartate receptor modulator.Neuropharmacology. 49, 1077-87) The potentiation of [³H]MK-801 binding(5 nM; 22.5 Ci/mmol) to well washed rat cortical membranes (200 μg) wasmeasured under non-equilibrium conditions (15 min @25° C.) in thepresence of increasing concentrations of test compounds and 50 μMglutamate. Zero levels were determined in the absence of any glycineligand and in the presence of 30 μM 5,7 DCKA Maximal stimulation wasmeasured in the presence of 1 mM glycine, and 50 μM glutamate waspresent in all samples. The facilitation of [³H]MK-801 binding by testscompounds was calculated by using a 3 parameter log agonist vs. responseequation (Graph pad Prism, USA) and potency (EC₅₀, expressed in pM) andmaximal activity (% maximal stimulation) were calculated for the testcompound. Data for compound Z is provided in Table 2 below.

TABLE 2 MK-801 Glycine Site LTP: LTP LTP: LTP LTP: LTP Binding Assay:Rat, Augmen- Concen- Signifi- Com- Cortex EC50 tation tration cance,pound (M) (%) (uM) S or NS X 2.43E−09 75 1 NS

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications,websites, and other references cited herein are hereby expresslyincorporated herein in their entireties by reference.

1. A compound represented by formula I:

or a stereoisomer, an N-oxide, and/or a pharmaceutically acceptable saltthereof, wherein R_(b) is H; R is H or C₁-C₆ alkyl; R₁ is H; R₂ is H; R₃—CONR′R′, wherein R′ for each occurrence is independently selected fromH, tert-butoxycarbonyl, carbobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, acetyl, trifluoroacetyl, benzoyl, benzyl,p-methoxybenzyl, p-methoxyphenyl, 3,4-dimethoxybenzyl, triphenylmethyl,benzylidene, and p-toluenesulfonyl; and X is H, X′, —C₁-C₆ alkylene-X′,or -C₁-C₆ alkylene-C(O)—X′, wherein X′ is selected from the groupconsisting of: (i) heterocyclyl including from 3 to 6 ring atoms wherein1, 2, or 3 of the ring atoms are independently selected from the groupconsisting of N and O; and (ii) phenyl; wherein X′ is optionallysubstituted by one or more substituents independently selected from thegroup consisting of hydroxyl and C₁-C₆alkoxy. 2.-37. (canceled).
 38. Thecompound of claim 1, wherein R is H.
 39. The compound of claim 1,wherein R is methyl.
 40. The compound of claim 1, wherein one of R′ is Hand the other R′ is p-methoxyphenyl.
 41. The compound of claim 1,wherein each of R′ is H.
 42. The compound of claim 1, wherein X is H.43. The compound of claim 1, wherein X is X′.
 44. The compound of claim1, wherein X is p-methoxyphenyl.
 45. The compound of claim 1, wherein Xis -C₁-C₆ alkylene-X′.
 46. The compound of claim 1, wherein X is benzyl.47. The compound of claim 1, wherein X is —C₁-C₆ alkylene-C(O)—X′. 48.The compound of claim 1, wherein X is


49. A method of treating neuropathic pain, the method comprising:administering to a patient in need thereof a compound represented byformula (I):

or a stereoisomer, or an N-oxide, and/or a pharmaceutically acceptablesalt thereof, wherein: R_(b) is selected from the group consisting of H,halogen, hydroxyl, cyano and C₁-C₆ alkyl; R is H or C₁-C₆ alkyl; R₁ is Hor C₁-C₆ alkyl; R₂ is H or C₁-C₆ alkyl; R₃ is selected from the groupconsisting of H, C₁-C₆ alkyl, —OH, C₁-C₆ alkoxy, —CO₂H, and —CONR′R′,wherein R′ for each occurrence is independently selected from H, C₁-C₆alkyl, 9-fluorenylmethyloxycarbonyl, tert-butoxycarbonyl,carbobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, acetyl,trifluoroacetyl, benzoyl, benzyl, p-methoxybenzyl, p-methoxyphenyl,3,4-dimethoxybenzyl, triphenylmethyl, benzylidene, p-toluenesulfonyl,—C(O)OR₃₁ and C(O)R₃₂, wherein R₃₁ is selected from the group consistingof C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀cycloalkyl, —CH₂-C₃-C₁₀ cycloalkyl, —CH₂-phenyl, and —CH₂-pyridyl,wherein the C₃-C₁₀ cycloalkyl is optionally substituted with from 1-3independently selected C₁-C₃ alkyl; and the phenyl is optionallysubstituted with from 1-2 substituents independently selected from C₁-C₃alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, nitro, halo,SO₂Me, cyano, and —OC(O)CH₃; and R₃₂ is selected from the groupconsisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and pyridyl,wherein the phenyl is optionally substituted with from 1-2 substituentsindependently selected from C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy,C₁-C₃ haloalkoxy, nitro, halo, SO₂Me, cyano, and —OC(O)CH₃; and X is H,X′, —C₁-C₆ alkylene-X′, or —C₁-C₆ alkylene-C(O)—X′, wherein X′ isselected from the group consisting of: (i) C₃-C₆ cycloalkyl; (ii)heterocyclyl including from 3 to 6 ring atoms wherein 1, 2, or 3 of thering atoms are independently selected from the group consisting of N, O,and S; (iii) phenyl; and (iv) heteroaryl including from 5 to 6 ringatoms wherein 1, 2, or 3 of the ring atoms are independently selectedfrom the group consisting of N, O, and S; wherein X′ is optionallysubstituted by one or more substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁-C₆ alkyl and C₁-C₆ alkoxy. 50.The method of claim 49, wherein R_(b) is H; R is H or methyl; R₁ is H;R₁ is H; R₂ is H; one of R′ is H; and X is H.
 51. The method of claim49, wherein R_(b) is H; R is H or methyl; R₁ is H; R₁ is H; R₂ is H; oneof R′ is H; and X is benzyl, p-methoxyphenyl, or


52. The method of claim 49, wherein the neuropathic pain is acute. 53.The method of claim 49, wherein the neuropathic pain is chronic.
 54. Themethod of claim 49, wherein the neuropathic pain is associated withfibromyalgia.
 55. The method of claim 49, wherein the neuropathic painis associated with diabetic neuropathy.
 56. The method of claim 49,wherein the neuropathic pain is associated with herpes, HIV, traumaticnerve injury, stroke, post-ischemia, reflex sympathetic dystrophy,complex regional pain syndrome, spinal cord injury, sciatica, phantomlimb pain, and cancer chemotherapeutic-induced neuropathic pain.